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Malaria remains a significant infectious disease with even artemisinin-based therapies now facing resistance in the field. Development of new therapies is urgently needed, either by finding new compounds with unique modes of action, or by reversing resistance towards known drugs with 'chemosensitizers' or 'chemoreversal' agents (CRA). Concerning the latter, we have focused on the resistance mechanisms developed against chloroquine (CQ). We have synthesized a series of compounds related to previously identified CRAs, and found promising novel compounds. These compounds show encouraging results in a coumarin labeled chloroquine uptake assay, exhibiting a dose response in resensitising parasites to the antimalarial effects of chloroquine. Selected compounds show consistent potency across a panel of chloroquine and artemisinin sensitive and resistant parasites, and a wide therapeutic window. This data supports further study of CRAs in the treatment of malaria and, ultimately, their use in chloroquine-based combination therapies.

Original publication

DOI

10.1016/j.ejmech.2016.04.058

Type

Journal article

Journal

Eur J Med Chem

Publication Date

25/08/2016

Volume

119

Pages

231 - 249

Keywords

Antimalarial, Artemisinin-resistant, Chemoreversal, Chemosensitiser, Chloroquine, Chloroquine-resistant, Animals, Antimalarials, Biological Transport, Cell Line, Chemistry Techniques, Synthetic, Chloroquine, Dose-Response Relationship, Drug, Drug Design, Drug Resistance, Inhibitory Concentration 50, Mice, Models, Molecular, Molecular Conformation, Plasmodium falciparum, Structure-Activity Relationship